Immune dysregulation
Authors: Andrew Long, Anatole Kleiner, R John Looney
Journal: Journal of Allergy and Clinical Immunology (2023)

The understanding of immune dysregulation in many different diseases continues to grow. There is increasing evidence that altered microbiome and gut barrier dysfunction contribute to systemic inflammation in patients with primary immunodeficiency and in patients with rheumatic disease. Recent research provides insight into the process of induction and maturation of pathogenic age-associated B cells and highlights the role of age-associated B cells in creating tissue inflammation. T follicular regulatory cells are shown to help maintain B-cell tolerance, and therapeutic approaches to increase or promote T follicular regulatory cells may help prevent or decrease immune dysregulation. Meanwhile, novel studies of systemic-onset juvenile idiopathic arthritis reveal a strong HLA association with interstitial lung disease and identify key aspects of the pathogenesis of macrophage activation syndrome. Studies of hyperinflammatory syndromes, including the recently described multisystem inflammatory syndrome of children, characterize similarities and differences in cytokine profiles and T-cell activation. This review focuses on recent advances in the understanding of immune dysregulation and describes potential key factors that may function as biomarkers for disease or targets for therapeutic interventions. Future trials are necessary to address the many remaining questions with regards to pathogenesis, diagnosis, and treatment of autoimmune, inflammatory, and immunodeficiency syndromes. The understanding of immune dysregulation in many different diseases continues to grow. There is increasing evidence that altered microbiome and gut barrier dysfunction contribute to systemic inflammation in patients with primary immunodeficiency and in patients with rheumatic disease. Recent research provides insight into the process of induction and maturation of pathogenic age-associated B cells and highlights the role of age-associated B cells in creating tissue inflammation. T follicular regulatory cells are shown to help maintain B-cell tolerance, and therapeutic approaches to increase or promote T follicular regulatory cells may help prevent or decrease immune dysregulation. Meanwhile, novel studies of systemic-onset juvenile idiopathic arthritis reveal a strong HLA association with interstitial lung disease and identify key aspects of the pathogenesis of macrophage activation syndrome. Studies of hyperinflammatory syndromes, including the recently described multisystem inflammatory syndrome of children, characterize similarities and differences in cytokine profiles and T-cell activation. This review focuses on recent advances in the understanding of immune dysregulation and describes potential key factors that may function as biomarkers for disease or targets for therapeutic interventions. Future trials are necessary to address the many remaining questions with regards to pathogenesis, diagnosis, and treatment of autoimmune, inflammatory, and immunodeficiency syndromes. Immune dysregulation can manifest as autoimmunity, autoinflammation, allergy, or lymphoproliferation. In patients with inborn error of immunity (IEI), these are often referred to as noninfectious complications. Immune dysregulation has been reported in all major categories of IEI and may be the initial presentation of IEI.1Thalhammer J. Kindle G. Nieters A. Rusch S. Seppanen M.R.J. Fischer A. et al.Initial presenting manifestations in 16,486 patients with inborn errors of immunity include infections and noninfectious manifestations.J Allergy Clin Immunol. 2021; 148: 1332-1341.e5Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar, 2Mauracher A.A. Gujer E. Bachmann L.M. Gusewell S. Pachlopnik Schmid J. Patterns of immune dysregulation in primary immunodeficiencies: a systematic review.J Allergy Clin Immunol Pract. 2021; 9: 792-802.e10Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar, 3Resnick E.S. Moshier E.L. Godbold J.H. Cunningham-Rundles C. Morbidity and mortality in common variable immune deficiency over 4 decades.Blood. 2012; 119: 1650-1657Crossref PubMed Scopus (515) Google Scholar, 4Ho H.E. Cunningham-Rundles C. Non-infectious complications of common variable immunodeficiency: updated clinical spectrum, sequelae, and insights to pathogenesis.Front Immunol. 2020; 11: 149Crossref PubMed Scopus (67) Google Scholar In common variable immune deficiency (CVID), immune dysregulation rather than infection is the major cause of mortality.3Resnick E.S. Moshier E.L. Godbold J.H. Cunningham-Rundles C. Morbidity and mortality in common variable immune deficiency over 4 decades.Blood. 2012; 119: 1650-1657Crossref PubMed Scopus (515) Google Scholar Immune dysregulation is also seen in the much more common polygenetic immune-mediated inflammatory diseases (IMIDs). There are lessons to be learned from studies of IEI that are applicable to IMIDs, and vice versa. This review will focus on selective advances in immune dysregulation of relevance to clinical immunologists (Table I).Table IImportant concepts in immune dysregulationImpaired intestinal barrier function increases risk of autoimmunity1. In CVID, low IgA, low switched memory B cells, and increased CXCL10 levels are associated with complications.7Abyazi M.L. Bell K.A. Gyimesi G. Baker T.S. Byun M. Ko H.M. et al.Convergence of cytokine dysregulation and antibody deficiency in common variable immunodeficiency with inflammatory complications.J Allergy Clin Immunol. 2022; 149: 315-326.e9Abstract Full Text Full Text PDF Scopus (0) Google Scholar,8Ho H.E. Cunningham-Rundles C. Seeking relevant biomarkers in common variable immunodeficiency.Front Immunol. 2022; 13857050Crossref Scopus (0) Google Scholar2. In CVID, increased serum bacterial DNA and zonulin levels are associated with increased IFN-γ levels and complications of autoimmunity.9Ho H.E. Radigan L. Bongers G. El-Shamy A. Cunningham-Rundles C. Circulating bioactive bacterial DNA is associated with immune activation and complications in common variable immunodeficiency.JCI Insight. 2021; Crossref Scopus (5) Google Scholar3. Peripheral blood mononuclear cells from patients with X-linked agammaglobulinemia have a defective response to bacterial DNA that can be mimicked with a BTK inhibitor.9Ho H.E. Radigan L. Bongers G. El-Shamy A. Cunningham-Rundles C. Circulating bioactive bacterial DNA is associated with immune activation and complications in common variable immunodeficiency.JCI Insight. 2021; Crossref Scopus (5) Google Scholar4. Intestinal barrier dysfunction precedes development of inflammatory arthritis in RA and mouse models of collagen-induced arthritis (CIA).10Tajik N. Frech M. Schulz O. Schalter F. Lucas S. Azizov V. et al.Targeting zonulin and intestinal epithelial barrier function to prevent onset of arthritis.Nat Commun. 2020; 11: 1995Crossref PubMed Scopus (127) Google Scholar,11Matei D.E. Menon M. Alber D.G. Smith A.M. Nedjat-Shokouhi B. Fasano A. et al.Intestinal barrier dysfunction plays an integral role in arthritis pathology and can be targeted to ameliorate disease.Med (N Y). 2021; 2: 864-883.e9PubMed Google Scholar5. Prevention of barrier dysfunction ameliorates arthritis in CIA.10Tajik N. Frech M. Schulz O. Schalter F. Lucas S. Azizov V. et al.Targeting zonulin and intestinal epithelial barrier function to prevent onset of arthritis.Nat Commun. 2020; 11: 1995Crossref PubMed Scopus (127) Google Scholar,11Matei D.E. Menon M. Alber D.G. Smith A.M. Nedjat-Shokouhi B. Fasano A. et al.Intestinal barrier dysfunction plays an integral role in arthritis pathology and can be targeted to ameliorate disease.Med (N Y). 2021; 2: 864-883.e9PubMed Google ScholarABCs play an important role in autoimmune disease1. There is marked expansion of ABCs in patients with CVID and HIV, but similar expansion of ABCs is also seen in RA and SLE.26Keller B. Strohmeier V. Harder I. Unger S. Payne K.J. Andrieux G. et al.The expansion of human T-bethighCD21low B cells is T cell dependent.Sci Immunol. 2021; 6eabh0891Crossref Scopus (25) Google Scholar2. Induction of ABCs requires CD4 T cells and expression of CD40 ligand, IL-21, and IFN-γ.3. TH1 cells stimulate ABCs to produce the IFN-γ–induced chemokines CXCL9 and CXCL10.28Nakayama T. Yoshimura M. Higashioka K. Miyawaki K. Ota Y. Ayano M. et al.Type 1 helper T cells generate CXCL9/10-producing T-bet+ effector B cells potentially involved in the pathogenesis of rheumatoid arthritis.Cell Immunol. 2021; 360104263Crossref Scopus (6) Google Scholar4. ABCs are expanded in the lungs of CVID and granulomatous interstitial lung disease patients, and in the synovium of RA patients.26Keller B. Strohmeier V. Harder I. Unger S. Payne K.J. Andrieux G. et al.The expansion of human T-bethighCD21low B cells is T cell dependent.Sci Immunol. 2021; 6eabh0891Crossref Scopus (25) Google Scholar, 27Rakhmanov M. Keller B. Gutenberger S. Foerster C. 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Powers L. et al.Age-associated B cells appear in patients with granulomatous lung diseases.Am J Respir Crit Care Med. 2020; 202: 1013-1023Crossref Scopus (15) Google ScholarTreg and Tfr cells help mediate peripheral self-tolerance1. The second checkpoint for humoral tolerance is mediated by CD4 T cells recognizing self-antigen on B cells.33Samuels J. Ng Y.S. Coupillaud C. Paget D. Meffre E. Impaired early B cell tolerance in patients with rheumatoid arthritis.J Exp Med. 2005; 201: 1659-1667Crossref PubMed Scopus (0) Google Scholar,34Chen J.W. Schickel J.N. Tsakiris N. Sng J. Arbogast F. Bouis D. et al.Positive and negative selection shape the human naive B cell repertoire.J Clin Invest. 2022; Crossref Scopus (2) Google Scholar2. Neuritin, a neuropeptide secreted by Tfr cells, mediates suppression of autoantibody production and IgE production.40Gonzalez-Figueroa P. Roco J.A. Papa I. Nunez Villacis L. Stanley M. 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Clark S.J. de la Calle-Fabregat C. et al.Single-cell Atlas of common variable immunodeficiency shows germinal center-associated epigenetic dysregulation in B-cell responses.Nat Commun. 2022; 13: 1779Crossref PubMed Scopus (0) Google Scholar The implication is that environmental factors almost certainly play a major role. Recent articles have given us a more detailed picture of the role the microbiome plays in the immune dysfunction in IEI and IMIDs, linking intestinal barrier dysfunction and immune activation by microbial products to the development of noninfectious complications (Fig 1). Multi-omics has been used to take a fresh look at biomarkers of noninfectious complications in CVID patients.7Abyazi M.L. Bell K.A. Gyimesi G. Baker T.S. Byun M. Ko H.M. et al.Convergence of cytokine dysregulation and antibody deficiency in common variable immunodeficiency with inflammatory complications.J Allergy Clin Immunol. 2022; 149: 315-326.e9Abstract Full Text Full Text PDF Scopus (0) Google Scholar Soluble CD14, a marker of monocyte activation, was increased in patients with complications and correlated with elevated cytokines, lower levels of serum IgA, and especially with lower levels of IgA and IgM antibodies binding to lipopolysaccharide. Unsupervised machine learning analysis of all data found that the top 3 contributors to cluster assignment were high CXCL10 (a chemokine induced by IFN-γ), low antibodies (both total isotype and LPS specific) and low isotype-switched memory B cells. These data are consistent with a model in which defects in humoral immunity, especially IgA, lead to barrier dysfunction, translocation of bacteria, activation of both the innate and the adaptive arms of the immune system, and tissue infiltration and/or autoimmunity. The clinical importance of these and other biomarkers in CVID was recently reviewed.8Ho H.E. Cunningham-Rundles C. Seeking relevant biomarkers in common variable immunodeficiency.Front Immunol. 2022; 13857050Crossref Scopus (0) Google Scholar In another recent article, serum bacterial DNA, which was elevated in CVID and X-linked agammaglobulinemia (XLA) patients compared to healthy controls, appeared to play a key role in immune activation.9Ho H.E. Radigan L. Bongers G. El-Shamy A. Cunningham-Rundles C. Circulating bioactive bacterial DNA is associated with immune activation and complications in common variable immunodeficiency.JCI Insight. 2021; Crossref Scopus (5) Google Scholar Sequencing indicated gut commensal bacterial were the source of the circulating bacterial DNA. Zonulin and intestinal fatty acid binding protein, two markers of small intestinal permeability defects, were also elevated in CVID versus health controls. Moreover, serum bacterial DNA was significantly higher in CVID patients with complications. CVID patients with complications also had increased serum levels of IFN-γ. Interestingly, in vitro activation of peripheral blood mononuclear cells with bacterial DNA induced greater IFN-γ production in CVID patients with complications, suggesting in vivo priming. The authors point out that the finding of endotoxin in CVID serum has been inconsistent in earlier studies. In this study, endotoxin was not found in serum despite using 4 different assays. Thus, bacterial DNA in serum is a biomarker for CVID with complications and may be the microbial factor that activates innate immunity. A second important part of this study involved patients with XLA. While patients with XLA also had significantly increased serum bacterial DNA, they did not have increased sCD14, LBP, zonulin, or intestinal fatty acid binding protein. Moreover, an inhibitor of Bruton tyrosine kinase (BTK) blocked bacterial DNA–induced IFN-γ production in normal peripheral blood mononuclear cells. Thus, the mutant BTK in XLA patients may explain their lower rate of noninfectious complications compared to patients with CVID. Intestinal barrier dysfunction has also been reported in patients with IMIDs. Moreover, recent studies have found targeting intestinal barrier disruption can treat systemic inflammation.10Tajik N. Frech M. Schulz O. Schalter F. Lucas S. Azizov V. et al.Targeting zonulin and intestinal epithelial barrier function to prevent onset of arthritis.Nat Commun. 2020; 11: 1995Crossref PubMed Scopus (127) Google Scholar,11Matei D.E. Menon M. Alber D.G. Smith A.M. Nedjat-Shokouhi B. Fasano A. et al.Intestinal barrier dysfunction plays an integral role in arthritis pathology and can be targeted to ameliorate disease.Med (N Y). 2021; 2: 864-883.e9PubMed Google Scholar Zonulin has recently been reported to be elevated not only in patients with rheumatoid arthritis (RA) but also in a subset of patients with pre-RA (anti-CCP positive but no synovitis).10Tajik N. Frech M. Schulz O. Schalter F. Lucas S. Azizov V. et al.Targeting zonulin and intestinal epithelial barrier function to prevent onset of arthritis.Nat Commun. 2020; 11: 1995Crossref PubMed Scopus (127) Google Scholar Moreover, patients with pre-RA that progressed to RA over the course of 12 months had elevated levels of zonulin at baseline. Because of controversy about the zonulin assay,12Fasano A. Zonulin measurement conundrum: add confusion to confusion does not lead to clarity.Gut. 2021; 70: 2007-2008Crossref Scopus (7) Google Scholar these results were corroborated using 2 established assays for small intestinal barrier dysfunction: first, expression of tight junction proteins in biopsy samples of the terminal ileum, and second, the ratio of lactulose absorption to mannitol absorption. In mouse models of inflammatory arthritis, the authors also found increased zonulin; these results were corroborated using lactulose/mannitol absorption, and increased absorption of fluorescein isothiocyanate (aka FITC)-dextran. Of note, in these mouse models, zonulin began to increase before synovitis occurred. There is a synthetic peptide, larazotide, that blocks the increase in intestinal permeability induced by zonula occludin toxin (aka ZOT) or zonulin. In these animal models of inflammatory arthritis, larazotide decreased intestinal permeability, arthritis score, and periarticular bone loss. Of note, larazotide is already being used in human trials.13Hoilat G.J. Altowairqi A.K. Ayas M.F. Alhaddab N.T. Alnujaidi R.A. Alharbi H.A. et al.Larazotide acetate for treatment of celiac disease: a systematic review and meta-analysis of randomized controlled trials.Clin Res Hepatol Gastroenterol. 2022; 46101782Crossref Scopus (4) Google Scholar Other interventions to block the increase in intestinal permeability—such as the short chain fatty acid butyrate and cannabinoid receptor inhibitors—had similar effects on intestinal permeability and arthritis score. Most intriguingly, the authors used an animal model to track T-cell migration (using a UV light–activated transgenic tag) to demonstrate that T cells migrate from the gastrointestinal (GI) tract to the synovial tissue of animals with inflammatory arthritis. Thus, intestinal barrier dysfunction may license T cells to migrate into target tissues. Recently a second article has confirmed increased small bowel permeability in RA and also found an expansion of small bowel homing cells in peripheral blood (CCR9+α4β7+) that correlated well with disease activity (DAS28).11Matei D.E. Menon M. Alber D.G. Smith A.M. Nedjat-Shokouhi B. Fasano A. et al.Intestinal barrier dysfunction plays an integral role in arthritis pathology and can be targeted to ameliorate disease.Med (N Y). 2021; 2: 864-883.e9PubMed Google Scholar The importance of B cells expressing T-bet in autoimmune disease was first demonstrated in 2002, using a murine lupus model with B-cell–specific T-bet deletion.14Peng S.L. Szabo S.J. Glimcher L.H. T-bet regulates IgG class switching and pathogenic autoantibody production.Proc Natl Acad Sci U S A. 2002; 99: 5545-5550Crossref PubMed Scopus (369) Google Scholar That same year, an association between autoimmune cytopenias and increased CD21low B cells in CVID was reported.15Warnatz K. Wehr C. Drager R. Schmidt S. Eibel H. Schlesier M. et al.Expansion of CD19hiCD21lo/neg B cells in common variable immunodeficiency (CVID) patients with autoimmune cytopenia.Immunobiology. 2002; 206: 502-513Crossref PubMed Scopus (0) Google Scholar While studying the role of sex and aging on the immune system, Philippa Marrack’s lab observed a subset of B cells expressing the myeloid markers CD11c and CD11b that increase with age in female mice.16Rubtsov A.V. Rubtsova K. Fischer A. Meehan R.T. Gillis J.Z. Kappler J.W. et al.Toll-like receptor 7 (TLR7)-driven accumulation of a novel CD11c+ B-cell population is important for the development of autoimmunity.Blood. 2011; 118: 1305-1315Crossref PubMed Scopus (399) Google Scholar This population was also expanded in young, healthy autoimmune prone mice and in women with RA. Thus, this subset was termed age-associated B cells, or ABCs, and this abbreviation is often still used.17Cancro M.P. Age-associated B cells.Annu Rev Immunol. 2020; 38: 315-340Crossref PubMed Scopus (105) Google Scholar A companion article from Michael Cancro’s lab identified a CD21low murine B-cell subset associated with aging.18Hao Y. O’Neill P. Naradikian M.S. Scholz J.L. Cancro M.P. A B-cell subset uniquely responsive to innate stimuli accumulates in aged mice.Blood. 2011; 118: 1294-1304Crossref PubMed Scopus (294) Google Scholar Subsequent studies demonstrated CD21lowCD11+ B cells express T-bet and have linked these cells to both murine and human autoimmunity and chronic infections.19Myles A. Sanz I. Cancro M.P. T-bet+ B cells: a common denominator in protective and autoreactive antibody responses?.Curr Opin Immunol. 2019; 57: 40-45Crossref PubMed Scopus (13) Google Scholar, 20Rubtsova K. Rubtsov A.V. Cancro M.P. Marrack P. Age-associated B cells: a T-bet–dependent effector with roles in protective and pathogenic immunity.J Immunol. 2015; 195: 1933-1937Crossref PubMed Scopus (120) Google Scholar, 21Sanz I. Wei C. Jenks S.A. Cashman K.S. Tipton C. Woodruff M.C. et al.Challenges and opportunities for consistent classification of human B cell and plasma cell populations.Front Immunol. 2019; 10: 2458Crossref PubMed Scopus (148) Google Scholar, 22Phalke S. 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Frede N. et al.The TH1 phenotype of follicular helper T cells indicates an IFN-gamma–associated immune dysregulation in patients with CD21low common variable immunodeficiency.J Allergy Clin Immunol. 2018; 141: 730-740Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar Expansion of TH1 was associated with increased IFN-γ production and with the accumulation of T-bet+CD21low B cells in peripheral blood and lymph nodes. Of note, a recent article reported a healthy individual with T-bet human deficiency having “largely normal” humoral immunity but lacking CD21lowCD11c+ B cells.25Yang R. Avery D.T. Jackson K.J.L. Ogishi M. Benhsaien I. Du L. et al.Human T-bet governs the generation of a distinct subset of CD11chighCD21low B cells.Sci Immunol. 2022; 7eabq3277Crossref Scopus (0) Google Scholar Therefore, interventions directed at reducing T-bet may be more targeted than B-cell depletion with anti-CD20 or anti-CD19 antibodies, and may mitigate immune dysfunction without blocking normal protective humoral responses. The association between T cells and T-bet+CD21low B cells has recently been analyzed in great detail.26Keller B. Strohmeier V. Harder I. Unger S. Payne K.J. Andrieux G. et al.The expansion of human T-bethighCD21low B cells is T cell dependent.Sci Immunol. 2021; 6eabh0891Crossref Scopus (25) Google Scholar